TOXICOLOGY
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2024
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IF 4.8
Hong-Yu Fu,Yue Li,Han Cui,Jiu-Zhi Li,Wan-Xue Xu,Xi Wang,Rui-Feng Fan
Mercuric chloride (HgCl 2 ), a widespread environmental pollutant, induces ferroptosis in chicken embryonic kidney (CEK) cells. Whereas activating transcription factor 4 (ATF4), a critical mediator of oxidative homeostasis, plays a dual role in ferroptosis, but its precise mechanisms in HgCl 2 -induced ferroptosis remain elusive. This study aims to investigate the function and molecular mechanism of ATF4 in HgCl 2 -induced ferroptosis. Our results revealed that ATF4 was downregulated during HgCl 2 -induced ferroptosis in CEK cells. Surprisingly, HgCl 2 exposure has no significant impact on ATF4 mRNA level. Further investigation indicated that HgCl 2 enhanced the expression of the E3 ligase beta-transducin repeat-containing protein (β-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of β-TrCP, with miR-15b-5p downregulation observed in HgCl 2 -exposed CEK cells. Importantly, miR-15b-5p mimics suppressed β-TrCP expression and reversed HgCl 2 -induced cellular ferroptosis. Mechanistically, HgCl 2 inhibited miR-15b-5p, and promoted β-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidant-related target genes and promoted ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/β-TrCP/ATF4 axis in HgCl 2 -induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl 2 nephrotoxicity.
研究领域:
毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2020
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IF 5.546
Tao Bai,Ruopeng Liang,Rongtao Zhu,Weijie Wang,Lin Zhou,Yuling Sun
Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe 2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Molecular & Cellular Toxicology
·
2023
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IF 1.7
Hou Xiaochao,Jiang Yujie,Xu Guiping
Background Colon cancer is a malignancy from digestive tract and remains the third most common cancer worldwide. Dexmedetomidine (DEX) can be used for postoperative analgesia in patients with colon cancer and also has biological activities such as anti-oxidative stress, anti-inflammation, and anti-cancer. Objective This study was designed to explore the functions and mechanism of DEX in regulating colon cancer cell proliferation, apoptosis, and autophagy. Results Dex reduced LoVo and HCT116 cell viability in a time- and dose-dependent way. Additionally, DEX suppressed colon cancer cell proliferation while promoting cell apoptosis and autophagy. Moreover, chloroquine (a compound used for inhibition of autophagy) reversed the promoting effect of DEX on colon cancer cell apoptosis. Furthermore, DEX activated the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway. PERK silencing inhibited DEX-induced cell apoptosis and autophagy. Conclusion This work revealed the anti-cancer effect of DEX treatment by inhibiting colon cancer cell proliferation while promoting cancer cell apoptosis and autophagy via the PERK/eIF2α/ATF4 pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Ziteng Yu,Xingpei Fan,Xinyi Zhao,Tianyue He,Xiaoyan Li,Haining Du,Meimei Zhao,Ruijiao Zhu,Mengcong Li,Ziyi Zhang,Fang Han
In recent years, the study of microplastics (MPs) and nanoplastics (NPs) and their effects on human health has gained significant attention. The impacts of NPs on lipid metabolism and the specific mechanisms involved remain poorly understood. To address this, we utilized high-throughput sequencing and molecular biology techniques to investigate how endoplasmic reticulum (ER) stress might affect hepatic lipid metabolism in the presence of polystyrene nanoplastics (PS-NPs). Our findings suggest that PS-NPs activate the PERK-ATF4 signaling pathway, which in turn upregulates the expression of genes related to lipid synthesis via the ATF4-PPARγ/SREBP-1 pathway. This activation leads to an abnormal accumulation of lipid droplets in the liver. 4-PBA, a known ER stress inhibitor, was found to mitigate the PS-NPs-induced lipid metabolism disorder. These results demonstrate the hepatotoxic effects of PS-NPs and clarify the mechanisms of abnormal lipid metabolism induced by PS-NPs.
研究领域:
环境科学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2024
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IF 9.2
Zeying Zhang,Di Yang,Xiaoyuan Yan,Qiujing Qiu,Jiajie Guo,Lihong Qiu
Background Differentiating dental pulp stem cells (DPSCs) into odontoblasts is a critical process for tooth self-repair and dentine‒pulp engineering strategies in the clinic. However, the mechanism underlying the regulation of DPSC odontoblastic differentiation remains largely unknown. Here, we demonstrated that BCL-2 interacting protein 3 (BNIP3)-dependent mitophagy is associated with importin subunit beta-1 (KPNB1)-activating transcription factor 4 (ATF4), which promotes DPSC odontoblastic differentiation. Methods The key genes involved in DPSC odontogenic differentiation were identified via bioinformatics. Stable silencing or overexpression of BNIP3 was performed to investigate its impact on DPSC differentiation in vitro ( n ≥ 3). To explore the role of BNIP3 in vivo, tooth root fragments loaded with the hydrogel-transfected DPSC complex were implanted into nude mice ( n ≥ 6). Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) polymerase chain reaction (PCR) were conducted to explore the binding site of ATF4 to the BNIP3 promoter ( n ≥ 3). Mitochondrial function experiments were performed to investigate the impact of ATF4-BNIP3 on mitochondria ( n ≥ 3). Immunoprecipitation (IP) mass spectrometry (MS) was used to investigate the interaction between ATF4 and its binding protein, KPNB1. Plasmids containing wild-type (WT)/mutant (MUT)-nuclear localization signal (NLS) forms of ATF4 were constructed to determine the specific amino acid residues recognized by KPNB1 and their effects on DPSC odontoblastic differentiation ( n ≥ 3). Results Compared with those in the control group, the levels of autophagy and mitophagy, especially BNIP3-dependent mitophagy, were greater in the DPSC odontoblastic differentiation group ( P < 0.05). Genetic silencing or overexpression of BNIP3 demonstrated that BNIP3 expression was positively correlated with the transition of DPSCs into odontoblasts both in vitro and in vivo ( P < 0.05). ATF4 regulates the expression of BNIP3 by directly binding to approximately −1292 to −1279 bp and approximately −1185 to −1172 bp within the BNIP3 promoter region, which is associated with mitophagy and mitochondrial reactive oxygen species (mtROS) levels ( P < 0.05). Moreover, ATF4 increased mitophagy, mitochondrial function, and cell differentiation potential via BNIP3 ( P < 0.05). Mechanistically, KPNB1 is a novel interacting protein of ATF4 that specifically recognizes amino acids (aa) 280–299 within ATF4 to control its translocation into the nucleus and subsequent transcription and differentiation processes ( P < 0.05). Conclusions We reported that the critical role of KPNB1/ATF4/BNIP3 axis-dependent mitophagy could provide new cues for the regeneration of the dental pulp‒dentin complex in DPSCs. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s11658-024-00664-9.
研究领域:
牙科学
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干细胞生物学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Hong Zhang,Kai Ren,Xiaoting Ni,Liwang Lin,Longyu Li,Wenlei Zhang,Zengliang Gao,Shiao Ren,Lili Fan,Xin Hai
Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been associated with the progression of multiple neurological disorders. This study demonstrates that the gut microbiota-derived metabolite TMAO potentiates As-induced neurotoxicity. Using network toxicology, we identified genes targeted by As and TMAO in depression, revealing significant enrichment in pathways related to apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress. In C57BL/6 mice, a high-choline diet exacerbated As-induced depressive behaviors, hippocampal damage, and astrocyte depletion, which were mediated by elevated TMAO levels. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) analysis confirmed that TMAO enhanced arsenic accumulation in plasma and brain tissues. In vitro experiments further demonstrated that TMAO exacerbated As-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis, and ferroptosis. Mechanistically, TMAO upregulated the ER stress PERK/eIF2α/ATF4 signaling pathway in response to As exposure. Knockdown of PERK attenuated As- and TMAO-mediated apoptosis and ferroptosis in cultured cells. Collectively, these findings indicate that dietary choline exacerbates arsenic-induced depressive-like phenotypes by increasing TMAO levels and activating the PERK/eIF2α/ATF4 signaling pathway.
研究领域:
神经毒理学
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环境卫生
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分子生物学
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神经科学
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毒理学
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营养科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
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2024
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IF 4.4
Junjie Chen,Weibin Fan,Jing Fan,Jiao Xie,Yan Wang,Yinhui Wang,Nengming Lin,Bin Lin
The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.
研究领域:
药理学
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细胞生物学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
FISH PHYSIOLOGY AND BIOCHEMISTRY
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2023
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IF 2.9
Pan En-Zhuang,Xin Yue,Li Xue-Qing,Wu Xin-Yu,Tan Xue-Lian,Dong Jing-Quan
The aim of this study was to investigate the splenic tissue damage of environmental biological drug avermectin to freshwater cultured carp and to evaluate the effect of silybin on the splenic tissue damage of carp induced by avermectin. A total of 60 carp were divided into 4 groups with 15 carp in each group, including the control group fed with basic diet, experimental group fed with basal diet and exposed to avermectin (avermectin group), experimental group fed with basal diet supplement silybin (silybin group), and experimental group fed with basal diet supplement silybin and exposed to avermectin (silybin + avermectin group). The whole test period lasted for 30 days, and spleen tissue was collected for analysis. In this study, H&E staining, mitochondrial purification and membrane potential detection, ATP detection, DHE staining, biochemical tests, qPCR, immunohistochemistry, and apoptosis staining were used to evaluate the biological processes of spleen tissue injury, mitochondrial function, oxidative stress, apoptosis, and endoplasmic reticulum stress. The results show that silybin protected carp splenic tissue damage caused by chronic avermectin exposure, decreased mitochondrial membrane potential, decreased ATP content, ROS accumulation, oxidative stress, apoptosis, and endoplasmic reticulum stress. Silybin may ameliorate the splenic tissue damage of cultured freshwater carp caused by environmental biopesticide avermectin by alleviating mitochondrial dysfunction and inhibiting PERK-ATF4-CHOP-driven mitochondrial apoptosis. Adding silybin into the diet becomes a feasible strategy to resist the pollution of avermectin and provides a theoretical basis for creating a good living environment for freshwater carp. Graphical Abstract
研究领域:
水产养殖
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毒理学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR HUMAN REPRODUCTION
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2023
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IF 4
Dong Xiaoyu,Xu Le,Wang Shuang,Jiao Xue,Yan Shumin,Huang Yufei,Yuan Ming,Wang Guoyun
Ferroptosis is an iron-dependent programmed cell death process characterised by the accumulation of lethal oxidative damage. Localised iron overload is a unique clinical phenomenon in ovarian endometriosis. However, the role and mechanism of ferroptosis in the course of ovarian endometriosis remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian endometriosis and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells. Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse endometriosis model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian endometriosis can activate autophagy-related ferroptosis in endometrial stromal cells, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the endometriosis environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian endometriosis.
研究领域:
妇科学
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细胞生物学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
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IF 5.858
Xiaohua Lu,Ge Yan,Sabine M. Klauck,Edmond Fleischer,Anette Klinger,Yoshikazu Sugimoto,Letian Shan,Thomas Efferth
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G 2 M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Wupei Pan,Xiaoyi Zou,Wenxin Tang,Xin Zheng,Minjuan Xie,Jie Zhou
Sodium aescinate (SA), derived from seeds of the Chinese herb Suoluozi ( Aesculus wilsonii Rehd.), has been linked to severe kidney injury during clinical use. We previously found that SA induces nephrocyte ferroptosis, and upregulation of glutathione peroxidase 4 (GPX4) or ferroptosis suppressor protein 1 (FSP1) expression only partially attenuates this toxic effect. In this study, we demonstrated that SA reduced cellular levels of hydrogen sulfide (H 2 S) and reduced coenzyme Q10 (CoQ10H 2 ), leading to impaired antioxidant defense and lipid peroxidation (LPO) in renal cells. Mechanistically, SA suppressed the expression of activating transcription factor 4 (ATF4), cystathionine γ-lyase (CTH) and sulfide: quinone oxidoreductase (SQOR). The SA-induced downregulation of CTH expression was attributed to the decreased recruitment of ATF4 to the cis -regulatory element (CRE) of the CTH promoter. ATF4 overexpression in SA-treated cells upregulated CTH expression, which elevated H 2 S and CoQ10H 2 levels, improved antioxidant defense, and reduced ferroptosis. Critically, CTH silencing completely abrogated these protective effects. Conversely, CTH or SQOR overexpression, or H 2 S supplementation restored CoQ10H 2 levels and protected against SA-induced ferroptosis. However, in SQOR-deficient cells, neither intervention rescued CoQ10H 2 nor alleviated nephrotoxicity despite increased H 2 S levels. Additionally, alternative oxidase (AOX) overexpression abolished the protective effect of the ATF4/CTH/SQOR axis by oxidizing CoQ10H 2 back to its inactive form. In conclusion, SA induced ferroptosis-mediated kidney injury by disrupting the ATF4/CTH/SQOR axis, leading to reduced CoQ10H 2 levels and impaired redox homeostasis. This study introduces this pathway as a novel therapeutic target for SA-induced nephrotoxicity.
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PubMed
高影响因子
IUBMB LIFE
·
2021
·Vol. 73
·期 9
·1180-1190
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IF 3.885
Jing Wang,Tao Wang,Yang Zhang,Jiaqi Liu,Jie Song,Yanlong Han,Lihong Wang,Shuang Yang,Lili Zhu,Rui Geng,Weimin Li,Xiaoguang Yu
The induction of ferroptosis is considered a new strategy for cancer treatment. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a post-transcriptional regulatory factor, whose low expression has been reported to link to the enhanced metastasis and angiogenesis of gastric cancer (GC). In this study, to explore the role of CPEB1 in ferroptosis, GC cells with overexpressed or silenced CPEB1 expression were treated with erastin, a classic ferroptosis inducer. The results showed that erastin dose-dependently decreased the viability of four GC cell lines (AGS, SNU-1, Hs-746 T, and HGC-27), suggesting that ferroptosis could be triggered in these GC cells. Interestingly, HGC-27 cells overexpressing CPEB1 were more sensitive to erastin, generated more lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and their glutathione peroxidase 4 (Gpx4) expression and GSH content were reduced. Contrarily, CPEB1-silenced AGS cells were more resistant to erastin. Mechanically, we demonstrated that CPEB1 overexpression reduced the expression of twist1, an inhibitor of activating transcription factor 4 (ATF4), thereby activating the ATF4/ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1) pathway (CHAC1, a molecule known to induce GSH degradation). Furthermore, re-expression of twist1 in GC cells impaired the effects of CPEB1 overexpression in presence of erastin. Additionally, similar to the in vitro results, the growth-inhibiting effects of erastin on GC xenografted tumors were also augmented by CPEB1 overexpression in vivo. Collectively, we demonstrate that CPEB1 facilitates erastin-induced ferroptosis by inhibiting twist1.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）